6-hydroxymethyl-3-oxo-4, 6-dienic steroids, acyl derivatives thereof, and process for preparing same



United States Patent Ofifice 3,375,167 Patented Mar. 26, 1968 6 HYDROXYMETHYL 3 X0 4,6 DIENIC STEROIDS, A'CYL DERIVATIVES THEREOF, AND PROCESS FOR PREPARING SAME Derek Burn, Michael George Lester, and Vladimir Petrow, London, England, assignors to The British Drug Houses Limited No Drawing. Filed May 20, 1965, Ser. No. 457,522 Claims priority, application Great Britain, June 3, 1964, 22,960/64; Se t. 1, 1964, 35,827/64 28 Claims. (Cl. 16774) This application is related to co-pending application S.N. 457,491 filed on May 20, 1965, and having a common inventor and common assignee.

This invention is for improvements in or relating to organic compounds and has particular reference to steroidal materials containing a hydroxymethyl substituent at C It is an object of the present invention to provide a new and general process for the preparation of a new series of steroidal products, namely, 6-hydroxymethyl-3- oxo-4,6-dienic steroids and acyl derivatives thereof, includingthe partial Formula I below.

The process of this invention is a discovery of considerable importance in the field of steroid technology. The 6-hydroxy (acyloxy)methyl-3-0xo-4,6-dienic steroids represent a hitherto unknown group of compounds, many of which possess valuable biological properties. Thus, for example, the derivatives of l'ifi-hydroxyandrostane which fall within the scope of the present invention may possess anabolic, androgenic, gonadotrophin-inhibiting, and claudogenic properties. The derivatives of l7a-acyloxypregnan-ZO-one which fall within the scope of the present invention may possess progestational and gonadotrophin-inhibiting properties. In conjunction with an oestrogen such for example as ethynyloestradiol, mestranol, 17a-chlorethynyl oestradiol and its 3-methyl and 3,17- dimethyl ether, 17-a-trifluoropropynyl oestradiol and its 3-metl1yl and 3,17-dimethyl ether, l7a-tritluorovinyl oestradiol and its B-methyl and 3,17-dimethyl ether, the compounds of the present invention and in particular 17aacetoxy-6-hydroxy (acyloxy) methylpregna-4,6-diene- 3,20-dione are of value as oral contraceptives. Such formulations may be administered as pills, tablets and other standard pharmaceutical formulations either in the conventional 2O days/month regimens or in sequential or serial regimens. The progestationally active 17a-acyloxypregnan-ZO-one derivatives are of value in various gynaecological disorders such as dysmenor'rhea, in endometriosis, disfunctional uterine bleeding, premenstrual tension syndrome, the postponement of normal menstruation, primary and secondary amenorrhea, sub-fertility, and inhibition of lactation, and may be administered in standard pharmaceutical formulations for these purposes. The derivatives of 16a,17a-isopropylidenedioxypregnan- 20-one and analogues thereof may likewise show progestational activity, anti-inflammatory activity,and antiendotoxic activity. Glucocorticoid activity will, in general, be shown by derivatives of 9a-fluoro-l1;8,17u,21-trihydroxy-pregnan-ZO-one,l7a,2l-dihydroxypregnane 11,20- dione, 1113,17a,2l-trihydroxypregnan-ZO-one and by the 2l-acyl and 17,2l-diacyl derivatives thereof. The compounds of the present invention also form exceptionally convenient intermediates for the preparation of therapeutically valuable 6-substituted-6-dehydro steroidal hormones of the androstane and pregnane series.

It is a further object of the present invention to provide pharmaceutical preparations of the biologically active materials in admixture with one or more solid or liquid pharmaceutically acceptable inert carriers.

The present invention provides new 6-hydroxyand acyloxy-methyl-3-oxo-4,6-dienic steroids including the partial Formula I below.

The invention provides the following new compounds:

17,8-acetoxy-6-hydroxymethyl l9 nor androsta-4,6-

dien-B-one which has claudogenic properties.

6 hydroxymethy-l6a,17wisopropylidenedioXypregna-4,6-

diene-3,20-dione which has progestational, claudogenic, anti-endotoxic and ovulation inhibition properties.

17ot-acetoxy-6-hydroxymethyl l6 methylenepregna-4,6- -diene-3,20 dione which has progestational, anti-endotoxic, anti-ovulatory properties.

21 acetoxy 7 6 acetoxymethyl-l7a-hydroxypregna-4,6- diene-3,11,20-trione which has anti-andotoxic properties.

17a acetoxy 6 hydoXymethylpregna-4,6-diene-3,20-

dione which has progestational, anti-ovulatory and gonadotrophin-inhibiting properties.

170: acetoxy 6 acetoXymethylpregna-4,6-diene-3,20-

dione which has progestational, anti-ovulat'ory and gonadotrophin-inhibiting properties.

17B acetoxy 6 hydroxymeth'ylandrosta'-4,-6-diene-3-one' which has anabolic and androgenic properties.

hydroxy 6 hydroxymethylandro'stat,6-diene-3,17-

dione which has anabolic and androgenic properties.

: acetoxy 6 hydroxymethyl-l6a-methylpregna 4,6-

diene-3,20-dione which has progestational, anti-ovula tory and gonadotrophin-inhibiting properties.

6-hydroxymethylandrosta-4,6-diene-3,l7-dione, which has androgenic and anabolic properties. I

17fi-hydroxy-6-hydroxymethyl-17a-methylandrosta- 4,6-dien-3-one, which has anabolic and androgenic properties.

1 1 fl-hydroxy-6-hydroxymethylpentara-4,6, 1 7 (20) -triene- 3,21-dione, which has claudogenic and anti-endotoxic properties.

21-acetoxy-1 1B,17e-dihydroxy-6-hydroxymethylpregna- 4,6-diene-3,20-dione, which has anti-endotoxic, antiovulator'y and gonadotrophin-inhibiting properties.

21 -acetoxy- 17 a -hydroxy-6-hydroxymethylpre gna-4,6-

diene-3,11,20-trione' and 2 1 -acet0xy-l 1,3, 17a-dihydroxy-9a-fluoro-6hydroxymethylpregna-4,6-diene-3,20-dione which have antiendotoxic properties.

17a-acetoxy-6-propionoxymethylpregna-4,6-diene-3,20-

dione, v

l7m-acetoxy-6-(fi-phenylpropionoxy)methylpregna-4,6-

diene'-3,20-dione, 17a-acetoxy-6-phenoxyacetoxymethylpregnatfl-diene- 3,20-dione, 17a-acetoxy-6-caproyloxymethylpregna-4,6-diene-3,20-

dione, 17a-acetoxy-6-acetoxyrnethyl-16-methylenepregna-4,6-

diene-3,20-dione, 17a-acetoxy-16-methylene-6-propionoxymethylpregna- 4,6-diene-3,20-dione, 17u-acetoxy-l6-methylene-6-(B-phenylpropionoxy) methylpregna-4,6-diene-3,20-dione, 17a-acetoxy-16-methylene-6-phenoxyacetoxymethylpregna-4,6-diene-3,20-dione and 17a-acetoxy-6-caproyloxymethyl-16-methylenepregna 4,6-diene-3,20-dione which have progestational, antiovulatory and gonadotrophin-inhibiting properties.

mula

CHzOR (I) 3 where R is H or an acyl group, which process comprises treating a 3-enol ether of a 6-hydroxymethyl steroid or acyl derivative thereof including the partial formula 611M011 (II) where R is as hereinabove defined and R is an alkyl, chloralkyl, hydroxyalkyl, cycloalkyl or alkaryl group with a dehydrogenating reagent.

An unexpected feature of the present invention is the rapidity and ease with which the 6-hydroxyor acyloxymethyl-3-oxo,4,6-dienic steroids (1) are formed from the corresponding 3-enol ethers (II).

Conversion of the 3-enol ether derivatives into the corresponding 6-hydroxyor acyloxy-methyl-3-oxo-4,6- dienic steroids may be effected by employing dehydrogenating agents under carefully regulated conditions.

In a preferred form of the present invention, the S-enol ether derivative is treated with 2,3-dichloro-5,6-dicyanobenzoquinone in an aqueous, water miscible, organic solvent such, for example, as aqueous acetone. Not less than one molecular proportion of the dehydrogenating agent is employed, and the reaction is generally complete within 10 minutes at room temperature.

Other water miscible organic solvents such, for example, as the lower aliphatic alcohols, dioxan, tetrahydrofuran, or dimethylformamide may also be employed but, in general, offer no advantage over the preferred form of the present invention.

Other dehydrogenating agents such, for example, as 2,3- dicyano-1,4-benzoquinone, 2,3-dibromo-5,G-dicyanobenzoquinone, chloranil, tetrachlorodiphenoquinone may also be employed but, in general, offer no advantage over the preferred form of the present invention.

At the completion of the reaction, the mixture is processed by methods well-known to those skilled in the art, and the 6-'hydroxy(acyloxy)methyl-3-oxo-4,6-dienic steroid (I) is isolated and purified by standard techniques.

According to the disclosure of copending application Ser. No. 457,491 and now abandoned filed concurrently herewith, there is provided an alternative process for the preparation of 6-hydroxyor acyloxy methyl-3-oxo-4,6- dienic steroids including the partial formula CHzO R where R is hydrogen or a lower acyl group containing up to six carbon atoms which process comprises reacting a corresponding 6-hydroxy (acyloxy) methyl 3-enol ether of a 3-oxo-A -steroid including the partial formula OHrOR (II) where R has the same meaning as above and R is a lower alkyl group with an equivalent amount of a halogen in an inert solvent and in the presence of at least one equiv alent amount of a strong proton acceptor.

The 6-hydroxy (acyloxy) methyl 3-enol ether of a 3-oxo-A -steroids (II) is dissolved in an inert solvent, such for example as methylene dichloride containing at least one equivalent proportion of a strong proton acceptor, such for example, as pyridine, and the solution treated, preferably in the temperature region of C., with one equivalent proportion of a halogen, preferably bromine, which may be dissolved in a convenient volume of an inert solvent, such as methylene dichloride. The mixture is permitted to stand for several minutes, and is then processed 'by extraction with a suitable solvent, such as ether. The crude reaction product thus obtained, may,

however, still contain halogen in a combined form. If this is the case, such a crude product may be warmed with a dehydrohalogenating agent, for example, pyridine when a halogen-free material will be obtained, which may then be purified by methods well known to those skilled in the art to give the required 6-hydroxy (acyloxy) methyl-3-oxo-4,6-dienic steroid.

There is also provided a process for the preparation of 6-acyloxymethyl-3-oxo-4,6-dicnic steroids including the partial Formula I Where R is an acyl group (containing up to 10 carbon atoms) which process comprises treating a 6-hydroxymethyl-3-oxo 4,6-dienic steroid including the partial Formula I Where R is H with an acylating reagent.

The acylating reagent as known to those skilled in the art may be for example the appropriate acid anhydride in a base such as pyridine, the appropriate acyl halide in a base such as pyridine or the appropriate acid and v toluene p-suiphonyl chloride in a base such as pyridine.

The process of the invention may be applied to 6- hydroxy (acyloxy) methyl 3-enol ethers of 3-oxo-A steroids derived from androstane, D-homoandrostane, 19- norandrostane, pregnane, D-homo pregnane and 19-norpregnane.

The 3-enol ether 6-hydroxyrnethyl starting materials (II) used in the present invention are described in our United States Patent No. 3,095,411. They are prepared from 6-formyl-3-enol ethers of steroidal 3-oxo-4-enes which may be additionally substituted by Hydroxyl and acyloxy groups and functional derivatives thereof in such positions as 11, 12, 16 (including 16- hydroxy methyl), l4, l5, l7, l8, 19, 20 and 21 (including the condensation products of 16a,17a-glycols with carbonyl components). Thiol groups at C are unaffected.

Carbonyl groups such for example as carbonyl groups at11,12,15,16,17,18 and 20.

Carbalkoxy groups at C C C C or in the sidechain.

Cyano groups at C C and C Alkyl groups, in particular Me groups at C C C C C and ethyl at C Alkenyl and alkynyl groups in particular vinyl and allyl, trifiuoropropynyl, trifluorovinyl, ethynyl, propynyl and chlorethynyl at C Methylene, halomethylene and ethylidene groups at C11, C16 and C17.

Groups such as benzylidene at C Methylene, haloand carboxy methylene at C :C

Lactone, ether and spiroketal residues: Spirolactone residues such as O-CO-CH -CH attached to C etheric groups at C and bridging C and C spiroketal moieties such as are present in diosgenone, 20,20-ethylenedioxy groups, 17,17-ethylenedioxy groups and similar functional derivatives.

Halogen groups and in particular chlorine and fluorine at C C and C Halomethyl at C Unsaturated linkages in particular at C C C C16 and 11 20)- Ketol groups in practicular acylated ketol groups at C16 C1'7: ir- 20 and 2o-21 Cortical side chains, both acylated, or converted into such protective derivatives as bismethylenedioxy, cycliccarbonates, cyclic acetonides or orthoformates.

Epoxides and halohydrins particularly at C The 3-enol ethers of the steroidal 3-oxo-4-enes are reacted with the Vilsmeier reagent in a solvent such as methylenedichloride at 0 C. followed by hydrolysis of the resulting iminium salts when the corresponding 6- formyl derivatives are obtained. Reduction of these 6- forrnyl derivatives as described in our United States Patent No. 3,095,411 for example catalytically with Raney nickel (rendered non-alkaline for example by ethyl acetate treatment) or with platinum on charcoal (in a sodium acetate buffer) yields the required 6-hydroxymethyl derivatives (II).

The process of invention may be applied to the 6-v hydroxy (acyloxy)methyl derivatives derived from the following steroids and acyl derivatives thereof:

testosterone and 19-nor derivatives thereof 2-methyltestosterone and 19-nor derivatives thereof l7a-methyltestosterone and 19-nor derivatives thereof 9( 11)-dehydro-l7a-methyltestosterone and 19-nor derivatives thereof 17a-propynyltestosterone, 17a-chlorethynyl, 17a-trifluoropropynyl, l7a-trifiuorovinyl testosterone and 19-nor derivatives thereof 17a-acyloxyproge-sterones and 19-nor derivatives thereof 9 1 l )-dehydro-17a-acyloxyprogesterones 16-methyl-17a-acyloxyprogesterones, 16-halomethy1-17aacyloxyprogesterones 9 1 1 -dehydro-16-rnethyl-17u-acvloxyprogesterones 16-methylene-17a-acyloxyprogesterones, 16-halomethylenel 7a-acyloxyprogesterones I 9 1 1 )-dehydro-16-methylene-l7a-acyloxyprogesterones 17 a-acyloxy- 1 6-ethylideneprogesterones 16a,17a-dimethylmethylenedioxyprogesterone 9(11)-dehydro-16a,17m-dimethylmethylenedioxyprogesterone cortisone 16-rnethylcortisone, 16-halomethylcortisone and the 21- fiuoro derivatives thereof ZI-methylcortisone and the 21-fiuoro derivatives thereof 16-methylenecortisone, 16-halomethylenecortis0ne and the 21-fiuoro derivatives thereof 1ou-hydroxyhydrocortisone and the 16a,17a)-acetonide thereof hydrocortisone 16-rnethylhydrocortisone, 16-halomethylhydrocortisone and the 21-fiuoro derivatives thereof ZI-methylhydrocortisone and the 21-fluoro derivatives thereof 16-methylenehydrocortisone, 16-h'alomethylenehydrocortisone and the 21-fiuoro derivatives thereof 16a-hydroxyhydrocortisone and the 1601,1711) -acetonide thereof 17,21-dihydroxypregna-4,9 11)-diene-3,20-dione 16-methyl-17a,21-dihydr0xypregna-4,9 l 1)-diene-3 ,20-

dione 2l-methyl-170:,21dihydroxypregna-4,9(11)-dien'e-3,20-

dione 16-methylene-17a,21-dihydroxypregna-4,9( 1 l )-diene- 3,20-dione 16u-hydroxy-1704,21-dihydroxypregna-4,9('11)-diene- 3,20-dione and the (16,l7)-acetonide thereof 21-fiuoro-16a,17a-dihydroxypregna-4,9(11)-diene-3,20-

dione and the (16,17)-acetonide thereof 21-fiuoro-16a,17a-dihydroxypregna-4-ene 3 ,1 1,20-trione and the (16,17)-acetonide thereof 21-fluoro-11,16a,17a-trihydroxypregn-4-ene-3,20-dione and the 16,17) -acetonide thereof 21-hydroxypregna-4,17-dien-3-one 1 1-oxo-2l hydroxypregna-4,17-dien-3-one 1 1,21-dihydroxypregna-4,17-dien-3-one 9 1 1 )-dehydro 21 hydroxypregna-4,17-dien-3 -one 3-0xopregna-4,17-dien-21-oic acid (esters) 3,11-dioxopregna-4,17-dien-2'1-oic acid (esters) 1 1-hydroxy-3-oxopregna-4,17-dien-21-oic acid (esters) 9 11)-dehydro-3-oxopregna-4,17-dien-21-oic acid (esters) 2 1-fiuoro-17 u-aqyloxyprogesterones progesterone l6-methylp'rogesterone 1 1 l-oxoprogesterone 9 1 1 -dehydroprogesterone 21-methylprogesterone diosgenone 17a-cyano-17/8-hydroxyandrost-4-eu-3-one 16 (on and/3)-hydroxytestosterone and 19-nor derivatives l6-methyl-16,17-dehydroprogesterone 16-cyano-progesterone l6-carbalkoxyprogesterones 16-hydroxymethylprogesterone I 3-(3-oxo-17fl-hydroxyandrost-4-en-l7u-yl) propionic acid 5,6-dicyanobenzoquinone. pregna-4,6-diene-3,20-dione, M.P. l18-120 C., was ob- 2'1 -fiuoro progesterone testololactone 16-fiuoro-corticoid-s.

The 9a-fluoro derivatives'ofthe above llfi-hydroxy and 1 l-oxo-steroids.

Following is a description by way of example of methods of carrying the invention into effect.

Example IJ17a-acetoxy-6-hydr0xymethylpregna-4,6-

diene-3,20-di0ne ]D+ (chloroform),

Example 2 The process of Example 1 was repeated using aqueous ethanol in place of 95% aqueous acetone. 17aacetoxy-6-hydroxymethylpregna-4,6 vdiene 3,20 dione, M.P. 1l8-120 C. was obtained.

Example 3 The process of "Example 1 was repeated using 95% aqueous dioxan in place of 95% aqueous acetone. 17aaoetoxy 6 hydroxymethylpregna 4,6-diene-3,20-dione, M.P. 118120 C. was obtained.

Example 4 The process of Example 1 was repeated using 95% aqueous dimethylformamide in place of 95% aqueous acetone. acetoxy-6-hydroxymethylpregna-4,6-diene- 3,20-dione. M.P. 118l20-C. was obtained.

Example 5 The process of Example 1 was repeated using 2,3- dicyano-1,4-benzoquinone in place of 2,3-dichloro-5,6- dicyanobenzoquinone. 17cc acetoxy 6 hydroxymethylpregna-4,6-diene-3,20-dione, .M=P '1'1'8-120 C. was obtained.

:Example 6 The process of Example 1 was repeated using chloranil in place of 2,3-dichloro-5,6-dicyanobenzoquinone. 17macetoxy-6 hydroxymethylpregna-4,6 diene -.3,20 dione, M.P. 118l20" C, was obtained.

Example 7 The process of Example 1 was repeated-using 2,3-dibromo-S,6-dicyanobenzoquinone in place of 2,3-dichloro- 17a-acetoxy-6-hydroxymethyltained.

Example 8 The process of Example 1 was repeated using tetrachlorodiphenoquinone in place of 2,3-dichloro-5,6-dicyanobenzoquinone. 17a-acetoxy-6hydroxymethylpregnae 4,6-diene-3,20-dione, M.P. 118120 C., was obtained.

Example 9.-17a-acet0xy-6-acet0xymethylpregna-4,6-- diene-3,20-dine COMe l OAc /\Me O l CHzOAG A solution of 17a-acetoxy-6-hydroxymethyl-3-methoxypregna-3,5-dien-20-one (4 g.) in a mixture of pyridine (10 ml.) and acetic anhydride (4 ml.) was allowed to stand overnight at room temperature. Water was then added dropwise to the stirred solution at 0 C. until crystals began to separate. More water was added gradually until precipitation of crystals was complete, The product was collected, washed and purified from aqueous acetone to give 17a-acetoxy-6-acetoxymethyl-3-methoxypregna-3, 5-dien-20-one, M.P. 117.5 to 118.5 C.

A212? 251 m (e=21,870)

A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.4 g.) in 40 ml. of 95% aqueous acetone was added dropwise during three minutes to a stirred solution Of17t1" acetoxy-6-acetoxymethy1-3-methoxypregna 3,5 dien-20- one (0.7 g.) in 70 ml. of 95% acetone. The mixture was stirred at room temperature for a further two minutes, poured into water and the product extracted with ether. The extract was washed with water, dilute aqueous sodi-- urn hydroxide, then with water and dried. Removal of the solvent, and crystallisation of the residue from methanol gave 17a acetoxy-6-acetoxymethylpregna-4,6-diene-3,20- dione, M.P. 189.5 to 190.5 C.

Treatment of the foregoing product (0.1 g.) in acetone (4 ml.) with 0.2 N aqueous sodium hydroxide (1 ml.) for 15 minutes at room temperature followed by dilution with water gave 17a-acetoxy-6-hydroxymethylpregna-4,6- diene-3,20-dione, M.P. 118-120 C., identical with that obtained in Example 1.

Example 10.-1 7B-acet0xy-6-hydroxymethyl-I 9-n0randr0sta-4,6-dien-3 -0ne OAc Mel OHiOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinor1e (0.2 g.) in 5 ml. of 95% aqueous acetone was added dropwise during two minutes to a stirred solution of 17 8- acetoxy-6-hydroxymethyl-3 methoxy 19 norandrosta- 3,5-diene (0.25 g.) in 25 ml. of 95% acetone. The mixture was stirred for a further two minutes at room temperature, then poured onto a column of neutral alumina. Elution with acetone afforded a gum which was purified by re-chromatography on neutral alumina in benzene solution. Elution with benzene-ether mixtures gave 17fi-acetoxy-6-hydroxymethyl-l9-norandrosta-4,6 dien 3 one, M.P. 188-190 C. (from aqueous methanol) 13 3 3380, 1745, 1675, 1635 and 1585 cutxEtOH 8 Example 11.-6-hydr0xym:ethyl-16m,1 7a-isopropylidenedioxypregna-4,6-diene-3,20-di0ne A 283 mu (6 22,340)

Example 12.-] 7a-acetoxy-6-hydroxymethyl-I 6-metlzylenep regna-4,6-dieire-3,20-di0ne t TCH: Me

JHsOH A solution of 2,3-dichloro-5,6=dicyanobenzoquinone (0.26 g.) in 10 ml. of aqueous acetone was added dropwise during two minutes to a stirred solution of 17 uacetoxy-6-hydroxymethyl 3 methoxy 16 methylenepregna-3,5-dien-20-one (0.5 g.) in 50 ml. of 95% aqueous acetone. The mixture was stirred for a further two minutes and poured onto a column of neutral alumina (40 g.). Elution with acetone gave a gum which was triturated with ether and crystallised from aqueous methanol to give 17a-acetoxy-6-hydroxymethyl 16 methylenepregna-4,6- diene-3,20-'dione, M.P. 178180 C., [a] -1l7.1 (chloroform) EtOE max.

Example 13.21-acet0xy-6-aoetoxymethyl-I7ahydroxypregna-4,6-diene-3,11,20-tri0ne CHzOAe acetic anhydride and pyridine overnight at room temperature) in 95% aqueous acetone (30 ml.). After 90 minutes the mixture was diluted with water andthe product was extracted into ether. Evaporation of the waterwashed and dried (Na- 80 extract afforded a residue which was crystallised from aqueous methanol to give 21- acetoxy-6-acetoxyrnethyl l7oc-hydroxypregna 4,6-diene- 3,11,20-trione,

1640 and 1585 cm- Example 14.-] 7 fi-acetoxy-6-hydr0xymethylandrosta- 4,6-dien-3-0ne A0 Mei CHaOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.4 g.) in 10 ml. of 95% aqueous acetone was added dropwise during two minutes to a stirred solution of 17,8- acetoxy-6-hydroxymethyl-3-methoxyandrosta,- 3,5 diene (0.5 g.) in 50 ml. of 95% aqueous acetone. The mixture was stirred for a further two minutes at room temperature, poured into Water, and the product isolated with ether. Purification by chromatography on neutral alumina, employing benzene-ether (4:1 as eluant, gave 175- acetoxy-6-hydroxymethylandrosta-4,6-dien-3-one, blades, M.P. 188-190 C., (from methylenedichloride-hexane), l ln AELOH max. 285 mu (6 23,120) Example -11fl-hydroxy-6-hydroxymethylandrosta- A solution of 6-formyl-11B-hydroxy-3-methoxyandrosta-3,5-dien-17-one (U.S. Patent No. 3,265,717) (1.3 g.) and sodium acetate (1.3 g.) in methanol (105 ml.) was added to a suspension of pre-reduced 5% platinum on charcoal (0.65 g.) in methanol (25 ml.) and the mixture was hydrogenated until one-molecular proportion of hydrogen had been absorbed. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ether and washed with water. Evaporation of the dried (Na SO ether solution afforded a residue'which was crystallised from aqueous methanol containing a trace of pyridine to give 11fi-hydroxy-6-hydroxymethyl-3-methoxyandrosta- 3,5-dien-17-one, M.P. 154-157 C., [a] =72.6 (chloroform),

AEtOH max.

A solution of 2,3-dichloro-5,6-dicyanobenzoquincne (0.225 g.) in 95 aqueous acetone (7.5 ml.) was added dropwise during 2 minutes to a stirred solution of 11,8- hydroxy-6-hydroxymethyl-3-methoxyandrosta 3,5 dienl7-one (0.33 g.) in the same solvent (30 ml.). The mixture was stirred at room temperature for a further 2 minutes and poured onto a column of neutral alumina (10 g.). Elution with acetone gave a solid residue which was 1'0 triturated with ether and crystallised from acetone-hexane to give 1l,B-hydroxy6 hydroxymethylandrosta-4,6-diene- 3,17-dione, M.P. 186-1'865" C., [a] +211 (chloroform),

EtOH max.

V 283 m... (e, 27,750 Example 16.6-hydr0xymethylandrosta-4,6-diene- CHEOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.09 g.) in aqueous acetone (2.5 ml.) was added dropwise over two minutes to a stirred solution of 6-hydroxymethyl-3-methoxyandrosta-3,5-dien-l7-one (0.12 g.) in 95% aqueous acetone. Stirring was continued for a further two minutes and the mixture was poured onto a column of neutral alumina (12 g.). Elution with acetone and crystallisation of the residue from aqueous methanol gave 6-hydroxymethylandrosta-4,6-diene-3,17-dione, M.P. 186-187 C., [a] +l25.9 (chloroform),

Example 1 7 7ot-acet0xy-6-hydroxymethyl-16amethylpregna-4,6-diene-3,20-di0*ne COMe Me ---OAc CHzOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.25 g.) in 95% aqueous acetone (10 ml.) was added 1 1 dropwise over two minutes at room temperature to a stirred solution of 11B-hydroxy-6-hydroxymethyl-3-methoxypentara-3,5,17-(20)-trien-21-one [total product obtained by treating 6-formyl-11fi-hyclroxy-3-methoxypentam-3,5,17(20)-trien-21-0ne (U.S. Patent No. 3,265,717) (0.5 g.) with lithium borohydride in dry tetrahydrofuran at room temperature for four minutes] (0.5 g.) in 95% aqueous acetone (50 ml.). After a further two minutes at room temperature the reaction mixture was poured onto a column of neutral alumina (40 g.). Elution with acetone atforded a residue which was crystallised from aqueous methanol to give 11fl-hydroxy-6-hydroxyrnethylpentara-4,6,l7(20)-triene-3,21-dione, 13i? 3500, 1675, 1630, 1595 cmr 16,200) and 284 m (22,800) Example 19.-21-acet0xy-1 1 8,1 7 u-dihydroxy-ti-hydroxymethylpregna-4,6-diene-3,20-dine EtOH max.

CHaOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.3 g.) in 95% aqueous acetone (15 ml.) was added dropwise over two minutes at room temperature to a stirred solution of 21-acetoxy-11B,17a-dihydroxy-6-hydroxymethyl-3-rnethoxyprenga 3,5 dien--one [total product obtained by hydrogenation of 21-acetoxy-1 15,171:- dihydroxy-6-formyl-3-methoxypregna 3,5 dien-ZO-one (Our U.S. Patent No. 3,095,411) (0.5 g.) in methanol solution in the presence of 5% platinum-charcoal] (0.5 g.) in 95% aqueous acetone (50 ml.). After a further one minute at room temperature the reaction mixture was poured onto a column of neutral alumina (30 g.). Elution with acetone and crystallisation of the residue from aqueous methanol gave 21-acetoxy-11,8,17a-dihydroxy-6-hydroxymethylpregna-4,6'diene-3,20-dione,

Nuiul 3450, 1735, 1720, 1675, 1635 and 159s (mt- 15,13? 284 m (6, 21,900) M.P. 134 C., [ab -168 (chloroform).

Example 20.17fl-hydroxy-6-hydr0xymethyl-17amethylandr0sta-4,6-dien-3-0ne on -"Me I OHzOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.4 g.) in 95% aqueous acetone ml.) was added dropwise over two minutes at room temperature to a stirred solution of 6-hydrox-ymethyl-3-methoxy-Hot-methylandrosta-3,5-dien-17fi-ol (0.65 g.) in 95% aqueous acetone (50 ml.). After a further one minute at room temperature, the reaction mixture was poured onto a column of neutral alumina (40 g.). Elution with acetone and evaporation of the solvent gave a residue which was crystalllised from aqueous methanol to give 17fi-hydroxy-6- hydroxymethyl-l7a-methylandrosta-4,6-dien-3-one,

:31? 3550, 1675, 1635, 1600 cm.*, A213? 283 mu (6, 24,000)

Example 21.-Tablets containing 4 mg. of 17a-acetaxy-6- hydroxymethylpregna-4,6-diene-3,20-di0ne and 0.05 mg. of ethinyloestradiol 17u-acetoxy 6 hydroxymethylpregna-4,6-diene- 3,20-dione mg 4 Ethinyloestradiol mg 0.05 Industrial methylated spirit, 66 OP, a suflicient quantity Lactose mg 105 Starch mg 11.7 Starch paste, 10 percent w./v., a sufficient quantity Magnesium stearate m 1.3 Starch, sufiicient to make mg 129.6

The ethinyloestradiol is dissolved in a suitable quantity The process of Example 1 is applied to 17fi-acetoxy- 3 benzyloxy 6 hydroxymethylandrosta 3,5 diene. 17B acetoxy 6 hydroxymethylandrost-a 4,6 dien 3- one, M.P. 188190 C., identical with that described in Example 14, is obtained.

Example 23 The process of Example 1 is applied to 17B-acetoxy- 3 (2 hydroxyethoxy) 6 hydroxymethylandrosta- 3,5 diene. 17B acetoxy 6 hydroxymethylandrosta- 4,6 dien 3 one, M.P. 188-190 C., identical with that described in Example 14 is obtained.

Example 24.6-hydr0xymeIhyZ-ZSD-spirosta- 4,6-dien-3-0ne A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.6 g.) in aqueous acetone (10 ml.) is added dropwise over two minutes to a stirred solution of 3 ethoxy-6- hydroxymethyl-Z5D-spirosta-3,S-diene [total product prepared by reduction of 3-ethoxy-6-formyl-2SD-spirosta- 3,5-diene (our U.S. Patent No. 3,114,750 (1 g.) with sodium borohydride in ethanol] (1 g.) in 95% aqueous acetone ml.) at room temperature. After a further 3-minntes at room temperature the reaction mixture is poured onto a column of neutral alumina (50 g.). Elution with acetone and evaporation of the eluate gave a residue which is crystallised from aqueous methanol to give 6- hydroxymethyl 25D spirosta 4,6 dien 3 one,

A532? 282 m (6, 2 2,500) and 23 3550, 1675, 1630 and 1595 cm.-

Example 25 .-1 7 3-acetoxy-6-hydr0xymethylandrosta- 4,6-dien-3-0ne OAc x551 285 m (6, 23,120) Example 26.-] 7a-acet0xy-6-hydroxymethylpregna- 4,6-diene-3,20-dine CO-Me M -02.:

l CHIOH 17a acetoxy 6 hydroxymethyl 3 methoxypregna- 3,5-dien-20-one (1.8 g.) in methylene dichloride (15 ml.) and pyridine (1.5 ml.) was cooled in ice, and the mixture stirred during the dropwise addition, over 5 minutes, of a solution of bromide (0.85 g.) in methylene dichloride ('8 ml.). Ether (100 ml.) was added, the ethereal mixture was washed with water, dilute hydrochloric acid, water, dilute aqueous sodium hydrogen carbonate, and finally with water to neutrality. The gum obtained after drying and removal of the solvents, was treated with pyridine (2 mL), and the solution heated on the steam bath for 5 minutes. Dilution with water (200 ml.) gave a gum which solidified upon trituration. The air-dried crude product was chromatographed on neutral alumina (3 0 g.). Fractions eluted with ether-acetone (1:1) and acetone were purified from methanol to give l7a-acetoxy-6-hydroxymethylpregna 4,6 diene 3,20 dione as needles, M.P. 115-122 C.

Example 2-7.--2I-acet0xy-6-hydroxymethylpregna 4,6,1 7(20) -t rien e-3,11-dione CHaQAc H Me i I CHaOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.3 g.) in aqueous acetone (10 ml.) was added dropwise during two minutes to a stirred solution of 21- acetoxy 6 hydroxymethyl 3 methoxypregna 3,5,17- (20)-trien-11-one (0.5 g.) in the same solvent (30 ml.). The mixture was stirred for a further two minutes and poured onto a column of neutral alumina (25 g.). Elution with acetone and purification of the product gave 21- acetoxy 6 hydroxymethylpregna 4,6,17(20) triene- 3,11-dione,

&3. 281 m (5, 22,800

Example 28.21-acet0xy-1 7 a-hydrbxy-6-hydroxymethylp-regna-4,6-diene-3,1 1,20-tri0ne A solution of 2,3o-dichloro-5,6-dicyanobenzoquinone (57 mg.) in 95% aqueous acetone (2.4 ml.) was added dropwise over 4 minutes to a stirred solution of 21- acetoxy 17a hydroxy 6 hydr0xymethyl-3-methoxypregna-3,5-diene-11,20-dione (121 mg.) in 95% aqueous acetone (12 ml.). The mixture was then filtered through a column of neutral alumina (8 g.). Elution with acetone gave material which on purification from acetone-hexane afi'orded crystals of 21-acetoxy-l7a-hydroxy-6-hydroxymethylpregna-4,6-diene-3,11,20-trione, M.P. 250 C., [a] +287 C., (in chloroform),

max.

Example 29.-21-acet0xy-110,17u-a'ihydroxy-9wfluoro- 6-hydroxymethylpv'egna-e ,6-diene-3,20-ali0ne I CHZOH max.

1 5 Example 30.21-acet0xy-6-hydr0xymethylpregna-4,6- dieize-3,20-dine CHaOAC A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.3 g.) in 10 ml. of 95% aqueous acetone was added .dropwise during two minutes to a stirred solution of 21 acetoxy-6-hydroxymethyl-3-methoxypregna-3,5-dien- .20-one (0.5 g.) in 50 ml. of 95% aqueous acetone. The mixture was stirred for a further two minutes and then filtered through a column of neutral alumina (40 g.). Elution with acetone gave material which was purified .from acetonehexane. 21-acetoxy-6-hydroxyrnethylpregna -4,6-diene-3,20-dione separated in crystals,

NM 283 my (6, 22,000)

max.

Example 31 7fl-hydroxy-6-hydroxymethyl-3-0x0- androsta-4,6-dien-17a-yl)propionic acid lactonte CHzOH A solution of 2,3-dichloro-5,6-dicyanobenzoquinone (0.1 g.) in 95% aqueous acetone (3 ml.) was added dropwise during two minutes to a stirred solution of 5-(175- hydroxy 3 ethoxy-6-hydroxymethylandrosta-3,5-dien- 17a-yl)propionic acid lactone (0.15 g.) in the same solvent (10 ml.). After a further two minutes the mixture was filtered through a column of neutral alumina g.). Elution with acetone gave -(17B-hydroxy-6-hydroxymethyl-3-oxo-androsta-4,6-dien-17a-yl)propionic acid lactone,

E22? 283 m (e, 21,700)

Example 32.17a-acetoxy-6-acetoxymethylpregna- 4,6-diene-3,20-di0n e C OMe Me oac CHZOAC 17rx-3CtOXy 6 hydroxymethylpregna-4,6-diene-3,20- dione (the product of Example 1) (1.0 g.) in pyridine (5 ml.) and acetic anhydride (2.5 ml.) was kept overnight at room temperature and the mixture then poured into iced water. The solid was collected, dried and crystallised from acetone-hexane to give l7a-acetoxy-6- acetoxymethylpregna 4,6 diene-3,20-dione, as prisms, M.P. 190-193 C.,.identical in all respects with the prodnot of Example 9.

C OMe Me 1 (EH10 C 0 0311s l7u-acetoxy 6 hydroxymethylpregna-4,6-diene-3,20- dione (the product of Example 1) (1.0 g.) in pyridine (3 ml.) and propionic anhydride (1.5 ml.) was heated on the steam bath for 2 hours. It was then poured into iced water (75 ml.). The product was purified from methanol to give 17a-acetoxy-6-propionoxymethylpregna-4,6-diene- 3,20-dione as cubes, M.P. 189 C.,

A319? 280 my, (6, 24,300)

Example 3 4 .-1 7a-acetoxy-6- B-ph eny lp ropionoxy methylpregna-4,6-diene-3,20-di0ne COMe 17a acetoxy 6 hydroxymethylpregna-4,6-dien-3,20- dione (the product of Example 1) (0.93 g.) in dry pyridine (2 ml.) was chilled in an ice-salt mixture. ti-Phenylpropionyl chloride (0.3 ml.) was added dropwise to the stirred mixture which was then stored overnight at 0 C. It was then diluted with iced water (40 ml.), and the gummy product allowed to settle. The supernatant liquor was decanted, and the residual gum triturated with ether to give a crystalline solid. This was purified from acetonehexane to give 17u-acetoxy-6-(fi-phenylpropionoxy)methylpregna-4,6-diene-3,ZO-dione, prisms, M.P. 183 C.,

Example 35.-17a-acet0xy-6-phen0xyacet0xymethylpregna-4,6-diene-3,20-diane C OMe Me -O Ac UHzOCOCHaO CsHs i513 277 ma (6, 24,000

1 7 Example 36 .1 7a-acet0xy-6-caproylaxymethyIpregna- 4,6-dierue-3,20-dine C OMB --OAc CHaOGO (CH2)ICHI 17a-acetoxy-6-hydroxymethylpregna 4,6 dime-3,20- dione (the product of Example 1 (1.0 g.) in dry pyridine (2.0 ml.) was stirred and cooled in ice-salt. n-Hexoyl chloride (0.36 ml.) was added dropwise, and the mixture stirred a further minutes and then stored overnight at 0 C. The'mixture was then diluted with iced-water (70 ml.). The product was isolated with benzene and chromatographed on neutral alumina (30 g.). Fractions eluted with benzene-ether (1:4) were triturated with hexane to give 17a-acetoxy-6-caproyloxymethylpregnaA,6- diene-3,20-dione,

Example 3 7 .1 7a-acet0xy-6-dcet0xymethyl-16-methylenepregna-4,6-diene-3,20-di0ne C OMB Me I -OAc CH: Me I CHzO C O CH:

17u-acetoxy-6-hydroxymethyl 16 methylenepregna- 4,6-diene-3,20-dione (the product of Example 12) (1.0 g.) in pyridine (4 ml.) and acetic anhydride (2 ml.) was heated at 100 C. for 1 hour. The mixture was poured into iced water (300 ml.) and the product isolated with ether. Purification from aqueous methanol gave 17a-acetoxy-6-acetoxymethyl 16 methylenepregna-4,6-diene- 3,20-dione, M.P. 85 C.,

A 279 my (6, 23,800)

Example 38.-17a-acetoxy-16-m ethylene-6 propionoxymethylpregna-4,6-diene-3,20-di0 ne GHnO CO 01H! l7a-acetoxy-6-hydroxymethyl-16-methylenepregna 4, 6-diene-3,20-di0ne (the product of Example 12) (0.5 g.) in pyridine (3 ml.) and propionic anhydride (1.5 ml.) was heated at 100 C. for 2 hours, and then poured into iced water (75 ml.). The product was purified from aqueous methanol and gave 17a-acetoxy-16-methylene 6- -propionoxymethylpregna-4,6-diene-3,20-dione as prisms, M.P. 117119.5 C.,

AEtOH max.

I 8 Example 39.J 7macet0xy-16-methylene-6 (fl-phenylpropz'onoxy methylpregna-4,6-diene-3,20-di0ne C OMe Me ---0 Ac m 279 my. (6, 25,100) Example 40.--17a-acetoxy-16-methyIene-6-phenoxyacetoxymethylpregna-4,6-diene-3,20-dione C OMe CHiC C O CHzOCuHs Phenoxyacetic acid (0.5 g.) in dry pyridine (14 ml.) was treated with toluene p-sulphonyl chloride (0.65 g.) and the mixture stirred and cooled in ice. 17a-acetoxy- 6-hydroxymethyl-16 methylenepregna-4,6 di-ene 3,20- dione (the product of Example 12) (0.5 g.) was then added, and the stirring and cooling; continued for 1 /2 hours. The mixture was poured into iced water and the gummy product purified from ethanol-to give 17a-acetoxy- 16-methylene-6-phenoxyacetoxymethylpregna-4,6 diene- 3,20-dione in the form of rods, M.P. 177181 C.,

xii? 276 mu (6, 24,000) Example 41.17a-acet0xy-6-capr0yl0xmethyl-I6-methylenepregna-4,6-diene-3,20-di0ne COMe I Me I CHBO CO(CH2)4CH:

17a-acetoxy-6-hydroxymethyl-l-methylenepregna 4, 6-diene-3,20-dione (the product of Example 12) (0.5 g.) was added to a stirred mixture of n-caproic acid (0.46 g.) and toluene-p-sulphonyl chloride 0.65 g.) in dry pyridine at 0 C. The mixture was stirred for 1 hour at 0 C., poured into cold water, and the product isolated with ether. Purification from aqueous methanol gave 17aacetoxy-6-n-caproyloxmethyl-16 methylenepregna 4,6- diene-3,20-dione, M.P. 67-73 0.,

P 280 mu (6, 22,900)

man.

We claim: 1. A process for the preparation of 6-hydroxyor acyloxymethyl-3 oxo-4,6-dienic steroids having the formula CHrOR I) I CHzOR where R and S are as hereinabove defined and R is an alkyl, chioralkyl, hydroxyalkyl, cycloalkyl. or alkaryl group, with a quinone dehydrogenating reagent.

2. A process as claimed in claim 1 wherein the 3- enol ether is treated-"with 2,3-dichloro-5,6-dicyanobenzoqui- H none in an aqueous water miscible organic solvent.

3. A process as claimed inclaim 2 wherein the Water miscible organic solvent is selected from the group consisting of acetone, lower aliphatic alcohols, dioxan, tetrahydrofuran and dimethylformamide.

4. A process as claimed in claim 1 wherein the dehydrogenating agent is selected from the group consisting of 2,3-dicyano-1,4-benzoquinone, 2,3-'dtibromo-5,6-dicyanobenzoquinone, chloranil and tetrachlorodiphenoquinone.

5. A compound selected from the group consisting of 6-hydroxymethyl-pregna-4,6-dienic-3,20diones and 6-hydroigymethylandrostat,6-dienic 3-ones and their corre- Sponding 6-acyl derivatives, wherein the said acyl group is'a residue of an alkanoic acid having up to" 10 carbon atoms. g I

6. A compound selected from the group consisting of 17a acetoxy 6 acyloxymethyl pregna 4,6 diene- 3,20-diones, wherein acyloxy is selected from the group consisting of acetoxy, propionoxy, fl-phenylpropionoxy,

phenoxyacetoxy; and caproyloxy, and the 16-methylene derivatives thereof.

7. 6 'hydroxyr'nethylandrosta 4,6 diene 3,17- dione.

8. 17,3 hydroxy 6 hydroxyrnethyl 17a methylandrosta-4,6-dien-3-one. A

9.115 hydroxy 6 hydroxyrnethylpentara 4,6, l7(20)-triene-3,21-dione.

10. 21 acetoxy 11,8,1711 dihydroxy 6 hydroxymethylpregna-4,6-diene3,20-dione.

11. 21 acetoxy 17a hydroxy 6 hydroxymethylpregna-4,6-diene-3 ,11,20trione.

12. 21 acetoxy 115,17 dihydroxy 9a fiuoro 6- hydroxymethylpregna-4,6-diene-3,20-dione.

13. 17a acetoxy 6 acetoxymethyl 16 methylenepregna-4,6-diene-3,20-dione.

14. 17,9 acetoxy 6 hydroxymethyl 19 nor androsta-4,6-dien-3-one.

1S. 6 hydroxymethyl 16a,17a-isopropylidenedioxypregna-4,6-diene-3,20-dione.

, 16. 17a acetoxy 6 hydroxymethyl 16 methylenepregna-4,6-diene-3,20-dione.

17. ;21 acetoxy 6 acetoxymethyl 17oz hydroxypregna 4,6-diene-3,11,2O-trione.

18. acetoxy 6 hydroxymethylpregna 4,6- diene-3,20-dione.

19. 17c: acetoxy 6 acetoxymethylpregna 4,6- diene-3,20-dion e.

20.1713 acetoxy 6 hydroxymethylandrosta 4,6- dien-3-one. i

21. 11B hydroxy 6 hydroxymethylandrosta 4,6- diene-3,l7-dione.

22. 17a acetoxy 6 hydroxymethyl 16a methylpregna-4,6-diene-3,20-dione.

23. '21 acetoxy 6 hydroxymethylpregna 4,6, 17(20)-triene-3,1l-dione.

24. 21 acetoxy 6 hydroxymethylpregna 4,6- diene-3,20-dione.

25. ,3 (17p hydroxy 6 hydroxymethyl 3 0x0- androsta-4,6-dien-17a-yl)propionic acid lactone.

26. A pharmaceutical preparation comprising a 6-hydroxyor acyloxymethyl-3-oXo-4,6-dienie steroid according to claim 5 in admixture with one or more solid or liquid pharmaceutically acceptable inert carriers.

27. A pharmaceutical preparation in-dosage unit form comprising 170: acetoxy 6 hydroxymethylpregna 4,6- diene'-3,20-dione in admixture with lactose, magnesium stearate and starch.

28. A pharmaceutical preparation according to 'claim 27 including also ethynyl oestradiol.

References Cited UNITED STATES PATENTS 3,257,388 6/19 66 Bowers et a1 260239.55

ELBERT L. ROBERTS,Primary Examiner.

l-I. FRENCH, Assistant Examiner. 

5. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6-HYDROXYMETHYL-PREGNA-4,6-DIENIC-3,20-DIONES AND 6-HYDROXYMETHYLANDROSTA-4,6-DIENIC-3-ONES AND THEIR CORRESPONDING 6-ACYL DERIVATIVES, WHEREIN THE SAID ACYL GROUP IS A RESIDUE OF AN ALKANOIC ACID HAVING UP TO 10 CARBON ATOMS.
 26. A PHARMACEUTICAL PREPARATION COMPRISING A 6-HYDROXY- OR ACYLOXYMETHYL-3-OXO-4,6-DIENE STEROID ACCORDING TO CLAIM 5 IN ADMIXTURE WITH ONE OR MORE SOLID OR LIQUID PHARMACEUTICALLY ACCEPTABLE INERT CARRIERS. 